Inhalation provides an effective means for treating a variety of lung diseases and conditions, such as bronchial asthma, emphysema, bronchitis, and interstitial lung disease. An important advantage of inhalation in treating lung diseases is the ability to deliver the drug directly to the site of drug action. A related advantage is the rapid onset of the therapeutic effect, compared with other routes of administration, such as intramuscular and oral routes. For drugs which are susceptible to breakdown in the gastrointestinal tract, or which otherwise cannot be administered orally, inhalation may be preferred for a variety of reasons over intravenous or intramuscular injection.
In one known method for administering a drug by inhalation, the drug is dissolved in a suitable solvent which can be aerosolized to form a small-particle mist. That is, the drug is dissolved in an aerosol composed of a drug solvent. This approach is also referred to herein as a drug-solute method. Where the drug is relatively water-soluble, the drug can be dissolved in an aqueous medium which can be aerosolized, for example, by a pneumatic nebulizer. A lipid-soluble drug may be dissolved in a propellant solvent, such as a freon-type solvent, for metered-dose aerosolization from a self-contained pressurized cannister.
Inhalation of the aerosol mist, by drawing the mist from the mouth, acts to deposit the aerosol particles in the respiratory tract. In general, the site of deposition of the particles in the respiratory tract will depend on particle size, with smaller particles favoring deposition at lower respiratory-tract regions. For example, mist particle sizes of greater than about 2-3 microns are deposited predominantly in the upper regions of the respiratory tract, whereas particle sizes less than about 2 microns favor deposition in the lower pulmonary regions, including deep-lung or parenchymal lung sites (Pityn, Chamberlain, Morgan, Goldberg, Scott, Yu).
The drug-solute approach has limited utility for administering lipid soluble drugs, particularly to the deep lung region of the respiratory tract. Although a pneumatic nebulizer can be operated under conditions which produce aqueous aerosol particles in the desired size range between about 1-2 microns, the limited solubility of a lipid-soluble drug in an aqueous medium limits the amount of drug which can be delivered. A propellant-solvent aerosol, although capable of dissolving the drug at relatively high concentration, is generally unable to reach the deep lung, in part because of rapid evaporation of the solvent and concomitant change in aerosol particle size.
Also known in the prior art are inhalation systems in which a drug is administered in particulate form, as a micronized suspension in a suitable carrier solvent system. Typically, the drug is a water-soluble compound which is suspended in micronized form in a fluorocarbon-type propellant solvent. This approach is generally unsuited for delivery of a lipid-soluble drug because of the difficulty in producing micronized particles in the submicron size, such as are required for forming 1-2 micron aqueous aerosol particle sizes needed for delivery to the deep lung.
One class of lipid-soluble drugs which have a number of therapeutic applications in treating lung conditions includes the corticosteroids. Several corticosteroids, such as beclomethasone diproprionate (BDP), dexamethasone, prednisone, and flunisolide, are used in the treatment of bronchial asthma and related bronchoconstriction conditions. Typically, the steroid compound is administered orally, for systemic uptake, or by inhalation, using a propellant-solvent aerosolizing device.
Corticosteroids are also the drug of choice for treating interstitial lung diseases (ILD). ILD form a heterogeneous group of nearly two hundred diffuse, noninfectious, nonmalignant, inflammatory, and often fatal disorders of the lower respiratory tract, resulting in pathological changes of alveolar tissue, in particular alveolar septum, epithelial and endothelial cells. These diseases progress from the initial acute stage through semichronic to chronic stage and are characterized by progressive development of extensive lung fibrosis or granulomatosis.
Untreated, most ILD are progressive and may rapidly become fatal. The patient's condition deteriorates due to an irreversible loss of alveolar-capillary units, causing the right side of the heart to become hypertrophic due to increased load. The ultimate result is general respiratory insufficiency with decreased delivery of oxygen to vital tissues such as heart and brain and, eventually, death.
Conventional therapy of ILD includes oral or systemic administration of multidoses of anti-inflammatory corticosteroids. One commonly used therapy for ILD is 40-80 mg/day of prednisone orally for one to two months. To control symptoms in many ILD chronic cases, follow-up treatment with lower doses (5-15 mg/day prednisone) is needed for weeks, years, or indefinitely. Still, favorable responses to such massive doses of steroids are achieved in only 20-60% of patients. Moreover, the large doses of steroids required when the drug is administered orally or systemically are accompanied by severe side effects which may compromise the benefit of long-term treatment.
Administration of corticosteroids by the inhalation route has the potential for overcoming the serious limitations of current oral or IV corticosteroid therapy. In particular, direct drug delivery to the deep lung would be effective at relatively low doses, and thus substantially mitigate side effects seen with long-term therapy. However, the limitations discussed above for aerosolizing lipid-soluble drugs, particularly for delivery to the deep lung, have prevented effective inhalation therapy by the drug in free form heretofore.